1. Project Summary/Abstract Electroconvulsive therapy (ECT) remains the gold-standard treatment for patients with depressive episodes. During a typical four-week ECT series, most depressive episodes remit, and formerly suicidal or psychotically depressed patients will resume their premorbid levels of functioning. Independent of the antidepressant effect of ECT, many patients experience debilitating but transient cognitive effects such as attention and memory def- icits. These unwanted side effects are particularly troubling for older patients who are more likely to have exist- ing cognitive deficits. Both the stimulus delivery (electrode placement, pulse amplitude, and pulse width) and seizure induction appear to work in synergy, but the underlying mechanism of action for successful response has yet to be fully elucidated. Moreover, further work is needed to understand the relationship between clinical improvement and cognitive impairment. This investigation will examine the clinical and neurocognitive impact of targeted medial temporal lobe engagement as a function of pulse amplitude, one of several variable factors influencing the ECT charge. The ECT charge is measured in millicoulombs (mC) and derived from multiplying pulse train duration, pulse-pair frequency, pulse width, and pulse amplitude. Pulse amplitude determines the induced electric field strength in the brain and is presently fixed at 900 milliamperes (mA) with no clinical or scientific justification. The central hypothesis of this investigation is that the optimal pulse amplitude for an indi- vidual patient will enhance neuroplasticity (clinical response) while minimizing the disruption of dominant hemi- sphere hippocampal cognitive circuitry (resulting in cognitive stability). Our preliminary data informs the dosage range between 600 and 800 mA. Pulse amplitudes outside of this range compromise efficacy (500 mA) or may increase risk of cognitive impairment (900 mA). The first aim of this investigation will identify the electric field strength and neuroplasticity associated with clinical response. Critically, this aim will establish the neuroplas- ticity threshold, which is defined as the electric field strength necessary to induce neuroplasticity. The second aim will detect the neural correlates of ECT-mediated cognitive changes, which may be related to disrupted dominant hemisphere long-term potentiation. The third aim will use data-driven dual regression to predict the optimal pulse amplitude for an individual patient. This contribution will be significant because the electric field, when manipulated by pulse amplitude, can subsequently maximize hippocampal neuroplasticity (efficacy) and minimize disrupted connectivity (cognitive stability) thus improving clinical outcomes. 2 !